Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1

描述（由申请方提供）：长期目标是阐明心磷脂（CL）代谢缺陷导致线粒体功能障碍和氧化应激代谢疾病发作的分子机制。CL是线粒体氧化磷酸化和ATP合成所需的关键线粒体磷脂。和胆固醇一样，CL也有“好”和“坏”之分，这是由亚油酸的含量决定的。好的CL的侧链主要由亚油酸组成，而坏的CL富含长链多不饱和脂肪酸。良好CL与不良CL的比率由“重塑”过程调节，该过程涉及磷脂酶的脱酰作用和溶血心磷脂酰基转移酶的再酰化作用。响应于活性氧（ROS）的有缺陷的CL重构导致不良CL的积累和线粒体功能障碍，其最近被确定为代谢疾病（包括糖尿病、肥胖、心血管疾病和衰老）中的常见缺陷。我们最近克隆了第一个酰基转移酶（ALCAT 1）参与有缺陷的CL重塑。我们的初步数据表明，ALCAT 1在线粒体功能障碍和胰岛素抵抗中起着致病作用，以响应ROS。本研究旨在验证ALCAT 1在氧化应激下导致CL重构缺陷导致线粒体功能障碍并加剧饮食诱导的肥胖症代谢并发症的假设。该提案将通过三个目标来实现：1）确定C2 C12或L 6稳定细胞系中ALCAT 1过表达引起的线粒体功能障碍和胰岛素抵抗的分子缺陷; 2）评估小鼠中ALCAT 1缺乏对与饮食诱导的肥胖相关的代谢并发症的生理作用; 3）确定ALCAT 1在CL重塑和磷脂代谢中的调节作用。目前工作的结果有望填补氧化应激引起的线粒体功能障碍与肥胖相关代谢并发症发病之间的缺失环节。拟议的工作还将有助于验证ALCAT 1作为糖尿病和肥胖症的新型药物靶点，从而激发制药行业开发代谢性疾病新型治疗方法的兴趣。公共卫生相关性：这项工作将有助于确定与肥胖相关的代谢并发症的根本原因，如糖尿病和心血管疾病。这项研究的结果预计将提供关键信息，说明抑制参与不良脂质合成的关键酶是否可以为糖尿病、肥胖和心血管疾病提供新的治疗方法。

DESCRIPTION (provided by applicant): The long term goal is to elucidate the molecular mechanisms by which defective cardiolipin (CL) metabolism contributes to the onset of mitochondrial dysfunction and metabolic diseases from oxidative stress. CL is a key mitochondrial phospholipid required for mitochondrial oxidative phosphorylation and ATP synthesis. Like cholesterols, there are "good" and "bad" CL, which is determined by the content of linoleic acid. The side chains of a good CL are dominated by linoleic acid, and a bad CL is enriched with long chain polyunsaturated fatty acids. The ratio of good vs. bad CL is modulated by a "remodeling" process that involves deacylation by phospholipases and reacylation by lysocardiolipin acyltransferases. Defective CL remodeling in response to reactive oxygen species (ROS) leads to accumulation of bad CL and mitochondrial dysfunction which have recently been identified as common defects in metabolic diseases including diabetes, obesity, cardiovascular diseases, and aging. We have recently cloned the first acyltransferase (ALCAT1) involved in defective CL remodeling. Our preliminary data demonstrate that ALCAT1 plays a causative role in mitochondrial dysfunction and insulin resistance in response to ROS. This project is test the hypothesis that defective CL remodeling by ALCAT1 in response to oxidative stress causes mitochondrial dysfunction and exacerbates metabolic complications in diet-induced obesity. The proposal will be accomplished by three Aims: 1) To identify molecular defects in mitochondrial dysfunction and insulin resistance caused by ALCAT1 overexpression in C2C12 or L6 stable cell lines; 2) To assess the physiological effects of ALCAT1 deficiency in mice on metabolic complications associated with diet-induced obesity; and 3) To determine the regulatory role of ALCAT1 in CL remodeling and phospholipid metabolism. Results from the current work are anticipated to fill in a missing link between mitochondrial dysfunction from oxidative stress and onset of metabolic complications associated with obesity. The proposed work will also help to validate ALCAT1 as a novel drug target for diabetes and obesity, and thereby stimulates pharmaceutical industry interests in development of novel treatment for metabolic diseases. PUBLIC HEALTH RELEVANCE: The proposed work will help to identify underlying causes of metabolic complications associated with obesity, such as diabetes and cardiovascular diseases. The results from the proposed research are anticipated to provide key information on whether inhibition of a key enzyme involved in synthesis of a bad lipid can provide a novel treatment of diabetes, obesity, and cardiovascular diseases.